Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy
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ABSTRACT:
PROVIDER: PRJNA928086 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23234526_1.fastq.gz | Fastqsanger.gz | |||
| SRR23234526_2.fastq.gz | Fastqsanger.gz | |||
| SRR23234527_1.fastq.gz | Fastqsanger.gz | |||
| SRR23234527_2.fastq.gz | Fastqsanger.gz | |||
| SRR23234528_1.fastq.gz | Fastqsanger.gz |
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Project description:BackgroundTraumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus-a structure that is highly susceptible to injury-has been implicated in the evolution of seizure development.MethodsUtilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2-4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE+) vs. those animals that did not (PTE-), which may be associated with epileptogenesis.ResultsCCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE+ compared to PTE- mice. We uniquely identified Cst3 as a PTE+-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE+ hilus.ConclusionsThese findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.
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Project description:We aimed to identify moleucalr sgnatures of astrocytes islaoted from the hippocampus in sham or CCI injured mice with or without spontaneous recurrent seizures
2023-05-15 | GSE223740 | GEO
Project description:The molecular mechanism underlying the role of hippocampal hilar interneuron degeneration in temporal lobe epilepsy (TLE) remains unclear. Especially, very few studies have focused on the role of neuronal nitric oxide synthase (nNOS, encoded by Nos1) containing hilar interneurons in TLE. In the present study, Nos1 conditional knockout mice were constructed, and we found that selective deletion of Nos1 in hilar interneurons rather than dentate granular cells (DGCs) triggered epileptogenesis. The level of nNOS was downregulated in patients and mice with TLE. Nos1 deletion led to excessive epilepsy-like excitatory input circuit formation and hyperexcitation of DGCs. Replenishment of hilar nNOS protein blocked epileptogenic development and memory impairment in pilocarpine-induced TLE mice. Moreover, chronic treatment with DETA/NONOate, a slowly released exogenous nitric oxide (NO) donor, prevented aberrant neural circuits of DGCs and the consequent epileptogenesis without acute antiseizure effects. Therefore, we concluded that NO donor therapy may be a novel anti-epileptogenesis strategy, different from existing antiseizure medications (ASMs), for curing TLE.
2024-10-21 | GSE274303 | GEO
Project description:Mesial temporal lobe epilepsy (MTLE) is the most common type of focal seizure disorder. In MTLE, seizures typically originate from a sclerotic hippocampus. Approximately one-third of patients do not respond to anti-seizure drugs and have few effective therapeutic options. Surgery to resect or ablate the affected temporal lobe is one such option, but it is not indicated or adequate for all individuals and can have adverse effects. Here, we report the development of an alternative cell therapy strategy for drug-resistant MTLE. The cell therapeutic is derived from a clinical-grade human embryonic stem cell line, and composed of cryopreserved post-mitotic medial ganglionic eminence (MGE)-type GABAergic inhibitory neurons of a predominantly pallial interneuron lineage. Single-dose intrahippocampal delivery of cryopreserved human pallial interneurons in a chronic mouse model of drug-resistant MTLE resulted in consistent and stable suppression of mesiotemporal seizures, with most animals becoming seizure-free. The grafted human interneurons distributed locally, matured, and persisted in the sclerotic hippocampus throughout the 8.5-month study. Pathological hallmarks of MTLE, such as hippocampal granule cell dispersion and sclerosis, were significantly reduced, and epileptic animal survival rates increased, after administration of the human interneurons. Suppression of seizure activity and amelioration of neuropathology were dose-dependent and suggested a broad therapeutic dosing range. No ectopic tissue or teratoma formation was detected after cell transplantation. Furthermore, behavioral abnormalities were not observed at any dose on a battery of assays. These findings support further development of human pallial MGE-type GABAergic interneuron cell therapy for the treatment of drug-resistant focal epilepsies.
2023-10-10 | GSE208672 | GEO
Project description:GABAergic interneuron in the cortex comprise a very heterogenous group. and it is critical to identify discrete interneuron types to understand how their contributions to behavior can be modulated by external and internal cues. However, molecular difinition of these interneuron cell groups has been difficult. Comparative analysis of different interneuron subtypes can provide us new candidate marker genes which could target more specific interneu?on cell group. Here we identify oxytocin responsive novel class of interneuron through our comparative analysis. We employed the bacTRAP strategy, which uses BAC transgenic mice expressing EGFP-tagged ribosomal protein L10a in specific cell populations, to affinity purify polysome-bound mRNAs from Nek7, Dlx1, Cort, Htr3a, Oxtr expressing cortical interneurons. We show that Oxtr expressing cells are a subtype of somatostatin positive interneurons. Three independent TRAP replicates were collected and total RNA from the immunoprecipitates or flow-through (input) whole cortex lysates were amplified and hybridized. Data were normalized with the GCRMA algorithm and replicates were averaged across conditions. We recommend filtering data to remove probe sets with normalized expression values less than 50 in at least one condition. Because the Nek7 BAC labels non-neuronal cells, we recommend to delete astrocytes and oligodendrocytes genes from the list using GSE13379 data.
2014-10-07 | E-GEOD-56996 | biostudies-arrayexpress
Project description:FK506-binding protein 51 (FKBP51, encoded by FKBP5) is a multisignaling cochaperone that regulates cellular stress responses and inflammatory signaling through the NF-κB pathway. Although FKBP51 is upregulated in reactive astrocytes, its role in epilepsy and excitotoxic neuroinflammation remains unknown. Excessive astrogliosis and impaired glutamate transporter-1 (GLT-1)-mediated glutamate clearance promote excitotoxicity and increase seizure susceptibility. Here, we investigated how both global and astrocyte-specific Fkbp5 deletions influence seizure susceptibility, astrogliosis, neuroinflammation, and cognition in male mice subjected to a kainic acid (KA)-induced epilepsy mouse model. Global Fkbp5 knockout (Fkbp5-KO) presented lower seizure activity along with decreased neuronal loss and astrogliosis in the hippocampus compared with the wild-type mice. Astrocyte-specific Fkbp5 conditional knockout (aFkbp5-cKO) mice similarly attenuated seizure severity, decreased astrogliosis, improved novel object recognition, and preserved GLT-1 expression in hippocampal CA3. Glia-neuron mixed cultures derived from Fkbp5-KO brains showed reduced NMDA-induced neurotoxicity and astrogliosis, accompanied by decreased NF-κB p65 phosphorylation. Notably, overexpression of an Fkbp5 quadruple mutant that disrupts the FKBP51-NF-κB interaction inhibited proinflammatory lipopolysaccharide-induced astrogliosis and NF-κB activation. Transcriptomic analysis of Fkbp5-KO hippocampi further confirmed suppression of NF-κB-driven inflammatory pathways. In summary, astrocytic FKBP51 mediates reactive astrogliosis and GLT-1 downregulation, linking excitotoxic neuroinflammation with seizure susceptibility and cognitive impairment, and represents a potential intervention target for epilepsy.
2026-02-02 | GSE293536 | GEO
Project description:Human inhibitory interneuron cell therapy for chronic focal epilepsy
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Project description:Astrogliosis is an inflammatory process by which astrocytes undergo morphological, transcriptional, and functional changes that primarily contribute to tissue healing and restore CNS homeostasis as a response to neuroinflammation. However, excessive astrocyte activation causes neuronal death, immune cell activation and infiltration, and chronic neuroinflammation. The advent of human induced pluripotent stem cell (hiPSC)-derived three-dimensional (3D) models has aided research of complex CNS processes by generating complex structures of neural cells able to decode the molecular mechanisms that trigger and sustain astrocyte activation and drive microenvironment remodeling in the human CNS. Despite depicting interactions between different brain cell types and their microenvironment, the lack of reproducibility, and immature/activated cell phenotypes typical of these models limit their utility to address neuroinflammation mechanisms. Here we establish a hiPSC-derived model of neuroinflammation to dissect cellular crosstalk along the neuroinflammatory axis. A methodology pioneered by our team was used, in which hiPSC-derived neural progenitors were cultured in perfusion stirred-tank bioreactors and differentiated into 3D neurospheroids composed of neurons, astrocytes, and oligodendrocytes. This model recapitulates specific features of the brain microenvironment, such as human brain-like ECM deposition and neuron-glia functional interactions. The neurospheroids were challenged with prototypical inflammatory factors reported to induce activation of astrocytes in mice models, namely TNF-α, IL-α, and C1q. By performing whole transcriptome analysis (RNAseq), we observed an upregulation of several inflammatory-related genes associated with TNF and NF-kB signaling (e.g., CXCL5, CCL2, TNAIP3, and NFKB2). Whole proteome analysis (SWATH-MS) also depicted the enrichment of proteins involved in cell response to stress and cytokine regulation, namely TXLNA, DCTN5, and NOLC1. Concomitantly, time course analysis of conditioned media from the stimulated neurospheroids exhibited increased secretion of inflammation-related cytokines (e.g., CCL2, CXCL10, IL-6, and IL-8). Astrocytes in challenged neurospheroids displayed an impaired capacity for clearance of extracellular glutamate and secretion of glutamine compared to the unstimulated control, indicating functional impairment and known molecular effects of TNF signaling. Together, these results further demonstrate astrocyte functionality within the neurospheroids, which undergo canonical astrogliosis events that are considered hallmarks of neuroinflammation. The human neurospheroid model described may contribute to better understand the mechanisms governing human astrogliosis and be used as a platform to study glial-neuron mature interactions during acute stimulation and inflammation.
2025-07-28 | PXD043835 | Pride
Project description:GABAergic interneuron in the cortex comprise a very heterogenous group. and it is critical to identify discrete interneuron types to understand how their contributions to behavior can be modulated by external and internal cues. However, molecular difinition of these interneuron cell groups has been difficult. Comparative analysis of different interneuron subtypes can provide us new candidate marker genes which could target more specific interneuｒon cell group. Here we identify oxytocin responsive novel class of interneuron through our comparative analysis. We employed the bacTRAP strategy, which uses BAC transgenic mice expressing EGFP-tagged ribosomal protein L10a in specific cell populations, to affinity purify polysome-bound mRNAs from Nek7, Dlx1, Cort, Htr3a, Oxtr expressing cortical interneurons. We show that Oxtr expressing cells are a subtype of somatostatin positive interneurons.
2014-10-07 | GSE56996 | GEO
Project description:Astrogliosis is an inflammatory process by which astrocytes undergo morphological, transcriptional, and functional changes that primarily contribute to tissue healing and restore CNS homeostasis as a response to neuroinflammation. However, excessive astrocyte activation causes neuronal death, immune cell activation and infiltration, and chronic neuroinflammation. The advent of human induced pluripotent stem cell (hiPSC)-derived three-dimensional (3D) models has aided research of complex CNS processes by generating complex structures of neural cells able to decode the molecular mechanisms that trigger and sustain astrocyte activation and drive microenvironment remodeling in the human CNS. Despite depicting interactions between different brain cell types and their microenvironment, the lack of reproducibility, and immature/activated cell phenotypes typical of these models limit their utility to address neuroinflammation mechanisms. Here we establish a hiPSC-derived model of neuroinflammation to dissect cellular crosstalk along the neuroinflammatory axis. A methodology pioneered by our team was used, in which hiPSC-derived neural progenitors were cultured in perfusion stirred-tank bioreactors and differentiated into 3D neurospheroids composed of neurons, astrocytes, and oligodendrocytes. This model recapitulates specific features of the brain microenvironment, such as human brain-like ECM deposition and neuron-glia functional interactions. The neurospheroids were challenged with prototypical inflammatory factors reported to induce activation of astrocytes in mice models, namely TNF-α, IL-α, and C1q. By performing whole transcriptome analysis (RNAseq), we observed an upregulation of several inflammatory-related genes associated with TNF and NF-kB signaling (e.g., CXCL5, CCL2, TNAIP3, and NFKB2). Whole proteome analysis (SWATH-MS) also depicted the enrichment of proteins involved in cell response to stress and cytokine regulation, namely TXLNA, DCTN5, and NOLC1. Concomitantly, time course analysis of conditioned media from the stimulated neurospheroids exhibited increased secretion of inflammation-related cytokines (e.g., CCL2, CXCL10, IL-6, and IL-8). Astrocytes in challenged neurospheroids displayed an impaired capacity for clearance of extracellular glutamate and secretion of glutamine compared to the unstimulated control, indicating functional impairment and known molecular effects of TNF signaling. Together, these results further demonstrate astrocyte functionality within the neurospheroids, which undergo canonical astrogliosis events that are considered hallmarks of neuroinflammation. The human neurospheroid model described may contribute to better understand the mechanisms governing human astrogliosis and be used as a platform to study glial-neuron mature interactions during acute stimulation and inflammation.
2025-07-02 | GSE243254 | GEO